Dokument: Understanding the aggregation of sickle hemoglobin (HbS) and identification of HbS aggregation inhibitors

Titel:Understanding the aggregation of sickle hemoglobin (HbS) and identification of HbS aggregation inhibitors
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URN (NBN):urn:nbn:de:hbz:061-20221024-082351-6
Dokumententyp:Wissenschaftliche Abschlussarbeiten » Dissertation
Autor: Olagunju, Maryam Olayemi [Autor]
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Dateien vom 14.10.2022 / geändert 14.10.2022
Beitragende:Jun.-Prof. Strodel, Birgit [Gutachter]
PD Dr. Weingart, Oliver [Gutachter]
Dewey Dezimal-Klassifikation:500 Naturwissenschaften und Mathematik » 540 Chemie
Beschreibung:Sickle cell disease commonly referred to as (SCD) is a blood disorder that is caused by the replacement of glutamic acid (E) with valine (V) at the sixth position of the β-globin chain of hemoglobin. This in turn leads to the aggregation of hemoglobin, this aggregation results in clinically observed symptoms known as “sickle cell crisis”. Hemoglobin sickle (HbS) is a variant of hemoglobin found in people with SCD. SCD is well investigated, but until recently, only three medications were approved by the drug authorities for the management of SCD and they do not fully address the underlying cause of the disease. Voxelotor, which is an HbS aggregation inhibitor, was recently approved by the FDA but it is highly expensive. Another alternative to the treatment of SCD is the highly expensive bone marrow transplant. Most of these treatments are not readily available in developing nations where the highest number of SCD patients are found. Therefore, there is an urgent need to develop cheap, effective and readil,y available drugs for the treatment of SCD. In this thesis, using computer aided drug design methods (CADD) we aim to understand the ag- gregation of HbS caused by the E6V mutation, identify protein-protein interaction hot-spots that can be prioritized in aggregation inhibitor designs and finally, identify prospective HbS aggregation inhibitors. First, using multiscale molecular dynamic simulations, the conformational dynamics of both wild-type and sickle hemoglobin at both monomeric and dimeric level were elucidated to assess their stability and highlight the effect of the E6V mutation on each structure. Next, we studied their aggregation into decamers and analyzed the protein-protein interactions of the ag- gregates in details. The condetails from these investigations revealed that the β-globin chains are less flexible in HbS than in HbA and the aggregation of HbS is not only driven by protein-protein interactions that are hydrophobic in nature but also electrostatic interactions are also important. Protein-protein contactS specific to HbS were identified in the first phase of the project, and these contacts were further exploited in the next phase to design inhibitors of HbS-aggregation. Using the knowledge obtained from the initial simulations, we performed high throughput virtual screening, using a library of of compounds including approved drugs, investigational drugs, natural products, and D-enantiomeric peptides followed by MD simulations in search of compounds that can bind to HbS and thereby inhibit its aggregation. From this investigation, we identified 16 promising organic molecules and 7 D-enantiomeric peptides. The organic molecules identified computationally, will be tested experimentally using both cell based in vitro assays to assess their HbS inhibitory properties.
Lizenz:Creative Commons Lizenzvertrag
Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz
Fachbereich / Einrichtung:Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:24.10.2022
Dateien geändert am:24.10.2022
Promotionsantrag am:27.04.2022
Datum der Promotion:30.05.2022
Status: Gast